(1S,3S,5S)-2-(tert-Butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid

Uses

(1S,3S,5S)-2-Boc-2-azabicyclo[3.1.0]hexane-3-carboxylic Acid is an impurity of Saxagliptin (S143500), which is a potent and selective reversible inhibitor of dipeptidyl peptidase-4, which is being developed for the treatment of type 2 diabetes. It is absorbed rapidly after oral administration and has a pharmacokinetic profile compatible with once daily dosing.

Synthesis

The general procedure for the synthesis of (1S,3S,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylic acid using (1S,3S,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid ester as raw material is as follows: the (1S,3S,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo [3.1.0]hexane-3-carboxylic acid (1.4 g) was dissolved in a mixed solvent of methanol (40 mL) and tetrahydrofuran (20 mL), 1N lithium hydroxide solution (10 mL) was added and the reaction was stirred at room temperature overnight. Upon completion of the reaction, the reaction mixture was acidified to pH 4.5 with 2N hydrochloric acid and stirring was continued for 15 min at room temperature. Subsequently, the reaction mixture was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to afford the target product (1S,3S,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (1.2 g, 96% yield, MNa+ = 250).

References

[1] Patent: WO2006/116157, 2006, A2. Location in patent: Page/Page column 114-115
[2] Patent: EP2272825, 2015, B1. Location in patent: Paragraph 0180; 0181
[3] Angewandte Chemie - International Edition, 2015, vol. 54, # 45, p. 13268 - 13272
[4] Angew. Chem., 2015, # 45, p. 13466 - 13470,4
[5] Patent: CN106928124, 2017, A. Location in patent: Paragraph 0037; 0083-0088